Methods for Treating Heart Arrhythmia

ABSTRACT

Methods and apparatus are provided for treatment of heart arrhythmia via renal neuromodulation. Such neuromodulation may effectuate irreversible electroporation or electrofusion, ablation, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential attenuation or blockade, changes In cytokine up-regulation and other conditions in target neural fibers. In some embodiments, such neuromodulation is achieved through application of an electric field. In some embodiments, such neuromodulation is achieved through application of neuromodulatory agents, of thermal energy and/or of high intensity focused ultrasound. In some embodiments, such neuromodulation is performed in a bilateral fashion.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of each of thefollowing co-pending United States patent applications:

(1) U.S. patent application Ser. No. 10/408,565, filed on Apr. 8, 2003(published as United States Patent Publication 2003/0216792 on Nov. 20,2003), which claims the benefit of U.S. Provisional Patent ApplicationNos. 60/442,970, filed Jan. 29, 2003; 60/415,575, filed Oct. 3, 2002 and60/370,190, filed Apr. 8, 2002.

(2) U.S. patent application Ser. No. 11/133,925, filed on May 20, 2005,which is a continuation of U.S. patent application Ser. No. 10/900,199,filed on Jul. 28, 2004 (now U.S. Pat. No. 6,978,174) which is acontinuation-in-part of U.S. patent application Ser. No. 10/408,665filed on Apr. 8, 2003.

(3) U.S. patent application Ser. No. 11/189,563, filed Jul. 25, 2005,which is a continuation-in-part of U.S. patent application Ser. No.11/129,765, filed on May 13, 2005, which claims the benefit of U.S.Provisional Patent Application Nos. 60/616,254, filed Oct. 5, 2004; and60/624,793, filed Nov. 2, 2004.

(4) U.S. patent application Ser. No. 11/266,993, filed on Nov. 4, 2005.

(5) U.S. patent application Ser. No. 11/363,867, filed Feb. 27, 2006,which (a) claims the benefit of U.S. Provisional Application No.60/813,589, filed on Dec. 29, 2005 (originally filed as U.S. applicationSer. No. 11/324,188), and (b) is a continuation-in-part of each of U.S.patent application Ser. No. 11/189,563, filed on Jul. 25, 2005, and U.S.patent application Ser. No. 11/266,933, filed on Nov. 4, 2005.

(6) U.S. patent application Ser. No. 11/504,117 filed on Aug. 14, 2006.

All of the foregoing applications publication and patent areincorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. In some embodiments, the present invention relates tomethods and apparatus for treating heart arrhythmia, such as atrialfibrillation.

BACKGROUND

Heart arrhythmia are conditions affecting the electrical system of theheart, causing irregular heart rhythms. Arrhythmia may originate in theatria or the ventricles of the heart, and they may induce tachycardia(fast heart rate) or bradycardia (slow heart rate). Atrial tachycardiainclude atrial fibrillation, atrial flutter, supraventriculartachycardia and Wolff-Parkinson-White syndrome. The irregular heartrhythm experienced during atrial fibrillation or other heart arrhythmiamay reduce the volume of blood pumped by the heart, and/or may put apatient at an elevated risk for stroke. Ventricular tachycardia includeventricular tachycardia, ventricular fibrillation and long QT syndrome.Bradycardia include sick sinus and conduction block. Pre-existing heartconditions, such as high blood pressure, valvular disease, coronaryartery disease and cardiomyopathy, may trigger heart arrhythmia bylowering blood supply to the heart, damaging heart tissue and/or othermechanisms.

Bradycardia may, for example, be treated with a pacemaker. Medicalpractitioners commonly treat tachycardia, such as atrial fibrillation,via electrical cardioversion with an external defibrillator. Animplantable cardioverter defribrillator additionally or alternativelymay be utilized. Medical practitioners also may utilize anti-arrhythmicsto control the patient's heart rhythm. Furthermore, they may recommendthat a patient take anti-coagulants, such as warfarin or aspirin, tothin the blood and reduce a risk of blood clot formation. Serioustachycardia may be treated via ablation of targeted regions of the heartthat impede aberrant electrical signals via a band of scar tissue.Patients who have undergone such ablation procedures may require apacemaker to maintain a regular heart rhythm.

The kidneys may play a role in atrial fibrillation, as well as otherheart arrhythmia or other cardio-renal diseases. Numerous academicstudies have noted an increase in sympathetic nerve activity duringatrial fibrillation. The functions of the kidneys can be summarizedunder three broad categories: (a) filtering blood and excreting wasteproducts generated by the body's metabolism; (b) regulating salt, water,electrolyte and acid-base balance; and (c) secreting hormones tomaintain vital organ blood flow. Without properly functioning kidneys, apatient may suffer water retention, reduced urine flow and anaccumulation of waste toxins in the blood and body.

Applicants have previously described methods and apparatus for treatingrenal and/or cardio-renal disorders by applying energy orneuromodulatory agents, either directly or indirectly, to neural fibersthat contribute to renal function. Such energy may, for example,comprise a monopolar or bipolar electric field, a thermal or non-thermalelectric field, a pulsed or continuous electric field, a stimulationelectric field, a beam of high intensity focused ultrasound, a thermalcooling energy and/or a thermal heating energy. See, for example,Applicants' co-pending U.S. patent application Ser. No. 11/129,765,filed on May 13, 2005; Ser. No. 11/189,583, filed on Jul. 25, 2005; Ser.No. 11/363,867, filed on Feb. 27, 2006; Ser. No. 11/368,836, filed onMar. 6, 2006; and Ser. No. 11/504,117, filed on Aug. 14, 2006.Additional methods and apparatus for achieving renal neuromodulation,e.g., via localized drug delivery (such as by a drug pump or infusioncatheter) or via use of a stimulation electric field, etc, aredescribed, for example, in co-owned and co-pending U.S. patentapplication Ser. No. 10/408,665, filed Apr. 8, 2003, as well as U.S.Pat. No. 6,978,174.

The energy or neuromodulatory agents may be delivered to the neuralfibers that contribute to renal function from apparatus positionedintravascularly, extravascularly, intra-to-extravascularly or acombination thereof. Furthermore, the energy or neuromodulatory agentsmay be delivered to neural fibers innervating a single kidney, or theymay be delivered bilaterally to neural fibers innervating both kidneys.In some embodiments, the energy may initiate denervation or other renalneuromodulation substantially athermally at least in part viairreversible electroporation or via electrofusion. In other embodiments,the energy may thermally induce the denervation or other renalneuromodulation via ablation or other mechanisms. Renal neuromodulationmay reduce renal sympathetic nerve activity.

In view of the foregoing, it would be desirable to provide novel methodsand apparatus for treating heart arrhythmia.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken in conjunctonwith the accompanying drawings, in which like reference characters referto parts throughout, and in which:

FIG. 1 is schematic view illustrating human renal anatomy.

FIG. 2A-2C are schematic isometric and end views showing the location ofthe renal nerves relative to the renal artery, and illustratingorienting of an electric field for selectively affecting the renalnerves.

FIGS. 3A and 3B are schematic diagrams illustrating, respectively, stepsin the treatment of heart arrhythmia via modulation of renal neuralfibers, and potential mechanisms by which renal neuromodulation maytreat arrhythmia.

FIG. 4 is a schematic side view, partially in section, illustrating anexample of an extravascular method and apparatus for renalneuromodulation.

FIGS. 5A-5D are schematic side views, partially in section, illustratingexamples of intravascular and intra-to-extravascular methods andapparatus for renal neuromodulation.

FIGS. 6A-6H are schematic side views, partially in section, illustratingmethods of achieving bilateral renal neuromodulation utilizing apparatusof the present invention, illustratively utilizing the apparatus of FIG.5A.

FIGS. 7A and 7B are schematic side views, partially in section,illustrating methods of achieving concurrent bilateral renalneuromodulation utilizing embodiments of the apparatus of FIG. 5A.

FIG. 8 is a schematic side view, partially in section, illustratingmethods of achieving concurrent bilateral renal neuromodulationutilizing an alternative embodiment of the apparatus of FIG. 4.

FIG. 9 is a schematic view illustrating an example of methods andapparatus for achieving renal neuromodulation via fully implantedapparatus.

DETAILED DESCRIPTION A. Overview

The present invention provides methods and apparatus for treating heartarrhythmia via modulation of neural fibers that contribute to renalfunction. The neuromodulation may be achieved, for example, via (a) amonopolar or bipolar electric field, (b) a thermal or a non-thermalelectric field, (c) a continuous or a pulsed electric field, (d) astimulation electric field, (e) localized drug delivery, (f) a highintensity focused ultrasound field or beam, (g) thermal techniques, (h)substantially athermal techniques, and/or (i) combinations thereof. Suchneuromodulation may, for example, effectuate irreversibleelectroporation or electrofusion, ablation, necrosis and/or inducementof apoptosis, alteration of gene expression, action potential blockadeor attenuation, changes in cytokine up-regulation and other conditionsin target neural fibers. Heart arrhythmia that potentially may betreated by the present invention include, but are not limited to, atrialarrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrialtachycardia, atrial fibrillation, atrial flutter, supraventriculartachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia,ventricular fibrillation, long QT syndrome, sick sinus, conduction blockand combinations thereof.

When the neuromodulatory methods and apparatus are applied to renalnerves and/or other neural fibers that contribute to renal neuralfunctions, it is expected that the neuromodulation can directly orindirectly increase urine output, decrease plasma renin levels, decreasetissue (e.g., kidney) and/or urine catecholamines (e.g.,norepinephrine), increase urinary sodium excretion, and/or control bloodpressure. Furthermore, the neuromodulatory effects may reduce renalsympathetic nerve activity, which may reduce the load on the heartand/or may provide a systemic reduction in sympathetic tone to reducethe patients susceptibility to heart arrhythmia, such as atrialfibrillation. Applicants believe that these or other changes may preventor treat heart arrhythmia or a host of other renal or cardio-renalconditions, such as congestive heart failure, hypertension, acutemyocardial infarction, end-stage renal disease, contrast nephropathy,other renal system diseases, and/or other renal or cardio-renalanomalies. The methods and apparatus described herein could be used tomodulate efferent or afferent nerve signals, as well as combinations ofefferent and afferent nerve signals.

In several embodiments, bilateral renal neuromodulation is effectuatedby modulating neural fibers that contribute to renal function of boththe right and left kidneys. Bilateral renal neuromodulation may provideenhanced therapeutic effect in some patients compared to unilateralrenal neuromodulation (i.e. modulation of neural fibers innervating asingle kidney). In some bilateral embodiments, concurrent modulation ofneural fibers that contribute to both right and left renal function maybe achieved. In other bilateral embodiments, the modulation of the rightand left neural fibers may be sequential. Bilateral or unilateral renalneuromodulation may be continuous or intermittent, as desired.

When utilizing an electric field to achieve desired neuromodulation, theelectric field parameters may be altered and combined in anycombination, as desired. Such parameters can include, but are notlimited to, voltage, field strength, power, pulse width, pulse duration,the shape of the pulse the number of pulses and/or the interval betweenpulses (e.g., duty cycle), etc. For example, suitable field strengthscan be up to about 10,000 V/cm, and the field may be continuous orpulsed. When pulsed, suitable pulse widths can be of any desired length,for example, up to about 1 second. Suitable shapes of the electricalwaveform include, for example, AC waveforms, sinusoidal waves cosinewaves, combinations of sine and cosine waves, DC waveforms, DC-shiftedAC waveforms, RF waveforms, square waves, trapezoidal waves,exponentially-decaying waves, or other combinations of wave shapes. Whenpulsed, the field may include at least one pulse, and in manyapplications the field includes a plurality of pulses. Suitable pulseintervals include, for example, intervals less than about 10 seconds.These parameters are provided as suitable examples and in no way shouldbe considered limiting. The electric field (or other energy modality orneuromodulatory agent) may achieve desired neuromodulation thermally orsubstantially athermally,

To better understand the structures of the devices described herein, andthe methods of using such devices, for renal neuromodulation in thetreatment of heart arrhythmia, it is instructive to examine the renalanatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes thekidneys K that are supplied with oxygenated blood by the renal arteriesRA, which are connected to the heart by the abdominal aorta AA.Deoxygenated blood flows from the kidneys to the heart via the renalveins RV and the inferior vena cava IVC. FIG. 2A illustrates a portionof the renal anatomy in greater detail. More specifically, the renalanatomy also includes renal nerves RN extending longitudinally along thelengthwise dimension L of the renal artery RA generally within theadventitia of the artery. The renal artery RA has smooth muscle cellsSMC that surround the arterial circumference and spiral around theangular axis θ of the artery. The smooth muscle cells of the renalartery accordingly have a lengthwise or longer dimension extendingtransverse (i.e., non-parallel) to the lengthwise dimension of the renalartery. The misalignment of the lengthwise dimensions of the renalnerves and the smooth muscle cells is defined as “cellularmisalignment.”

Referring to FIGS. 2B and 2C, the cellular misalignment of the renalnerves and the smooth muscle cells may be exploited to selectivelyaffect renal nerve cells with reduced effect on smooth muscle cells.More specifically, because larger cells require a lower electric fieldstrength to exceed the cell membrane irreversibility threshold voltageor energy for irreversible electroporation, embodiments of electrodes ofthe present invention may be configured to align at least a portion ofan electric field generated by the electrodes with or near the longerdimensions of the cells to be affected. In specific embodiments, thedevice has electrodes configured to create an electrical field alignedwith or near the lengthwise dimension L of the renal artery RA to affectrenal nerves RN. By aligning an electric field so that the fieldpreferentially aligns with the lengthwise aspect of the cell rather thanthe diametric or radial aspect of the cell, lower field strengths may beused to affect target neural cells, e.g., to ablate, necrose or fuse thetarget cells, to induce apoptosis, to alter gene expression, toattenuate or block action potentials, to change cytokine up-regulationan for to induce other suitable processes. This is expected to reducetotal energy delivered by the system and to mitigate effects onnon-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning an electric field with the lengthwise orlonger dimensions of the, target cells, the electric field may propagatealong the lateral or shorter dimensions of the non-target cells suchthat the electric field propagates at least partially out of alignmentwith non-target smooth muscle cells SMC). Therefore, as seen in FIGS. 2Band 2G, applying an electric field with propagation lines Li generallyaligned with the longitudinal dimension L of the renal artery RA maypreferentially cause electroporation (e.g., irreversibleelectroporation), electrofusion or other neuromodulation in cells of thetarget renal nerves RN without unduly affecting the non-target arterialsmooth muscle cells SMC. The electric field may propagate in a singleplane along the longitudinal axis of the renal artery, or may propagatein the longitudinal direction along any angular segment θ through arange of 0°-360°.

An electric neuromodulation system placed within and/or in proximity tothe wall of the renal artery may propagate an electric field having alongitudinal portion that is aligned to run with the longitudinaldimension of the artery in the region of the renal nerves RN and thesmooth muscle cells SMC of the vessel wall so that the wall of theartery remains at least substantially intact while the outer nerve cellsare destroyed, fused or otherwise affected. Monitoring elements may beutilized to assess an extent of, e.g., electroporation or temperaturechange, induced in renal nerves and/or in smooth muscle cells, as wellas to adjust electric field parameters to achieve a desired effect

C. Illustrative Schematic Diagrams of Steps and Potential Mechanisms byWhich Renal Neuromodulation May Treat Heart Arrhythmia

With reference to FIG. 3A, illustrative steps in one embodiment for thetreatment of heart arrhythmia, such as atrial fibrillation, viamodulation of neural fibers that contribute to renal function aredescribed. An energy delivery element is placed in proximity to thetarget renal neural fibers. Energy and/or a neuromodulatory agent isthen delivered to the target neural fibers via the energy deliveryelement or an agent delivery element. The energy and/or theneuromodulatory agent treats the heart arrhythmia. As shown by dottedline in FIG. 3A, the effects of the energy delivery optionally may bemonitored (e.g., via a thermocouple or other sensor), and monitoringdata optionally may be utilized in a feedback loop to adjust the energydelivery to treat the heart arrhythmia.

As seen in FIG. 3B, the neuromodulatory effects induced by the apparatusand methods of the present invention may reduce renal and/or systemicsympathetic nerve activity. A reduction in renal sympathetic activationmay induce hormonal changes that reduce renin secretion, which inhibitsAngiotensin conversion and reduces production of Aldosterone. Thesehormonal responses, coupled with direct neuronal controls, may increasesodium excretion, which in turn may increase fluid offload. These eventsmay reduce the pre-load on the heart. Furthermore, the neurohormonalchanges may reduce peripheral vascular resistance, which may reduceafter-load on the heart. The reduction in load on the heart may be usedin the treatment of heart arrhythmia, such as atrial fibrillation.Meanwhile, a reduction in systemic sympathetic tone may reduce thepatient's susceptibility to the heart arrhythmia.

Applicants believe that these or other changes might prevent or treatheart arrhythmia or a host of other renal or cardio-renal conditions,such as heart failure, hypertension, acute myocardial infarction,end-stage renal disease, contrast nephropathy, other renal systemdiseases, and/or other renal or cardio-renal anomalies for a period ofmonths, potentially up to six months or more. This time period may besufficient to allow the body to heal, thereby alleviating a need forsubsequent re-treatment. Alternatively, as symptoms reoccur, or atregularly scheduled intervals, the patient may return to the physicianfor a repeat therapy. The methods and apparatus described herein couldbe used to modulate efferent or afferent nerve signals, as well ascombinations of efferent and afferent nerve signals.

D. Illustrative Embodiments of Systems and Additional Methods forNeuromodulation

With reference to FIGS. 4 and 5, examples of systems and methods forrenal neuromodulation are described. FIG. 4 shows one embodiment of anextravascular electric field apparatus 200 that includes one or moreelectrodes configured to deliver an electric field to renal neuralfibers to achieve renal neuromodulation. The apparatus of FIG. 4 isconfigured for temporary extravascular placement; however, it should beunderstood that partially or completely implantable extravascularapparatus additionally or alternatively may be utilized. Applicants havepreviously described extravascular electric field (“e-field”) systems,for example, in co-pending U.S. patent application Ser. No. 11/180,563,filed Jul. 25, 2005.

In FIG. 4, apparatus 200 comprises a laparoscopic or percutaneouse-field system having a probe 210 configured for insertion in proximityto the track of the renal neural supply along the renal artery or veinor hilum and/or within Gerota's fascia under, e.g., CT or radiographicguidance. At least one electrode 212 is configured for delivery throughthe probe 210 to a treatment site for delivery of electric fieldtherapy. The electrode(s) 212, for example, may be mounted on a catheterand electrically coupled to a field generator 50 via wires 211. In analternative embodiment, a distal section of the probe 210 may have oneelectrode 212, and the probe may have an electrical connector to couplethe probe to the field generator 50 for delivering an electric field tothe electrode(s) 212.

The electric field generator 50 is located external to the patient. Thegenerator, as well as any of the embodiments of electrodes describedherein, may be utilized with any embodiment of the present invention fordelivery of an electric field with desired field parameters. It shouldbe understood that embodiments of field delivery electrodes describedhereinafter may be electrically connected to the generator even thoughthe generator is not explicitly shown or described with each embodiment.

The electrode(s) 212 can be individual electrodes that are electricallyindependent of each other, a segmented electrode with commonly connectedcontacts, or a continuous electrode. A segmented electrode may, forexample, be formed by providing a slotted tube fitted onto theelectrode, or by electrically connecting a series of individualelectrodes. Individual electrodes or groups of electrodes 212 may beconfigured to provide a bipolar signal. The electrodes 212 may bedynamically assignable to facilitate monopolar and/or bipolar energydelivery between any of the electrodes and/or between any of theelectrodes and an external ground pad. Such a ground pad may, forexample, be attached externally to the patient's skin, e.g., to thepatient's leg or flank. In FIG. 4, the electrodes 212 comprise a bipolarelectrode pair. The probe 210 and the electrodes 212 may be similar tothe standard needle or trocar-type used clinically for pulsed RF nerveblock. Alternatively, the apparatus 200 may comprise a flexible and/orcustom designed probe for the renal application described herein.

In FIG. 4, the percutaneous probe 210 has been advanced through apercutaneous access site P into proximity with a patient's renal arteryRA. The probe pierces the patient's Gerota's fascia F, and theelectrodes 212 are advanced into position through the probe and alongthe annular space between the patient's artery and fascia. Once properlypositioned, electric field therapy may be applied to target neuralfibers across the bipolar electrodes 212. Such electric field therapymay, for example, at least partially denervate the kidney innervated bythe target neural fibers, e.g., through irreversible electroporation ofcells of the target neural fibers and/or through thermal damage to thetarget neural fibers. The electrodes 212 optionally also may be used tomonitor the effects of the e-field therapy. After treatment, theapparatus 200 may be removed from the patient to conclude the procedure.

Referring now to FIGS. 5A-5D, embodiments of intravascular andintra-to-extravascular electric field systems are described. Applicantshave previously described intravascular electric field systems, forexample, in co-pending U.S. patent application Ser. No. 11/129,765,filed May 13, 2005, which has been incorporated herein by reference.Furthermore, applicants have previously described intra-to-extravascularfield systems, for example, in co-pending U.S. patent application Ser.No. 11/324,188 (hereinafter, “the '188 application”), filed Dec. 29,2005.

The intravascular embodiment of FIG. 5A includes an apparatus 300comprising a catheter 302 having a positioning element 304 (e.g., aballoon, an expandable wire basket, other mechanical expanders, etc.),shaft electrodes 306 a and 306 b disposed along the shaft of thecatheter, and optional radiopaque markers 308 disposed along the shaftof the catheter in the region of the positioning element 304. Theelectrodes 306 a-b, for example, can be arranged such that the electrode306 a is near a proximal end of the positioning element 304 and theelectrode 306 b is near the distal end of the positioning element 304.The electrodes 306 are electrically coupled to the field generator 50(see FIG. 4), which is disposed external to the patient, for delivery ofthe electric field therapy.

The positioning element 304 may comprise an impedance-altering elementthat alters the impedance between electrodes 306 a and 306 b during thee-field therapy, for example, to better direct the e-field therapyacross the vessel wall. This may reduce an applied voltage or a totalenergy required to achieve desired renal neuromodulation. Applicantshave previously described use of an impedance-altering element, forexample, in co-pending U.S. patent application Ser. No. 11/266,993,filed Nov. 4, 2005. When the positioning element 304 comprises aninflatable balloon, the balloon may serve as both a centering elementfor the electrodes 306 and as an impedance altering electrical insulatorfor directing an electric field delivered across the electrodes, e.g.,for directing the electric field into or across the vessel wall formodulation of target neural fibers. Electrical insulation provided bythe element 304 may reduce the magnitude of applied voltage or otherparameters of the electric field necessary to achieve desired fieldstrength or thermal effects at the target fibers.

The electrodes 306 can be individual electrodes independent contacts), asegmented electrode with commonly connected contacts, or a singlecontinuous electrode. Furthermore, the electrodes 306 may be configuredto provide a bipolar signal, or the electrodes 306 may be used togetheror individually in conjunction with a separate patient ground pad formonopolar use. As an alternative or in addition to placement of theelectrodes 306 along the central shaft of catheter 302, as in FIG. 5A,the electrodes 306 may be attached to the positioning element 304 suchthat they contact the wall of the renal artery RA. In such a variation,the electrodes may, for example, be affixed to the inside surface,outside surface or at least partially embedded within the wall of thepositioning element. The electrodes optionally may be used to monitorthe effects of e-field therapy, as described hereinafter. As it may bedesirable to reduce or minimize physical contact between the electricfield delivery electrodes and the vessel wall during delivery of thee-field therapy, e.g., to reduce the potential for injuring the wall,the electrodes 306 may, for example, comprise a first set of electrodesattached to the shaft of the catheter for delivering the e-fieldtherapy, and the device may further include a second set of electrodesoptionally attached to the positioning element 304 for monitoring theeffects of e-field therapy delivered via the electrodes 306.

In use, the catheter 302 may be delivered to the renal artery RA asshown, or it may be delivered to a renal vein or to any other vessel inproximity to neural tissue contributing to renal function, in a lowprofile delivery configuration, for example, through a guide catheter.Once positioned within the renal vasculature, the optional positioningelement 304 may be expanded into contact with an interior wall of thevessel. A thermal or non-thermal electric field that is continuous orpulsed is then generated by the field generator 50, transferred throughthe catheter 302 to the electrodes 306, and delivered via the electrodes306 across the wall of the artery. The e-field therapy modulates theactivity along neural fibers that contribute to renal function, e.g., atleast partially denervates the kidney innervated by the neural fibers.This may be achieved, for example, via irreversible electroporation,electrofusion and/or inducement of ablation, necrosis or apoptosis inthe nerve cells. In many applications, the electrodes are arranged sothat the electric field is aligned with the longitudinal dimension ofthe renal artery to facilitate modulation of renal nerves with littleeffect on non-target smooth muscle cells or other cells.

When utilizing intravascular e-field apparatus to achieveneuromodulation, in addition or as an alternative to central positioningof the electrode(s) within a blood vessel, the electrode(s) optionallymay be configured to contact an internal wall of the blood vessel.Wall-contacting electrode(s) may facilitate more efficient transfer ofan electric field across the vessel wall to target neural fibers, ascompared to centrally-positioned electrode(s). In several embodiments,the wall-contacting electrode(s) may be delivered to the vesseltreatment site in a reduced profile configuration, then expanded in vivoto a deployed configuration wherein the electrode(s) contact the vesselwall. In other embodiments, the electrode(s) may also be at leastpartially contracted to facilitate retrieval of the electrode(s) fromthe patient's vessel.

FIGS. 5B and 5C depict an illustrative embodiment of an intravascularapparatus having electrodes configured to contact the interior wall of avessel. The apparatus of FIGS. 5B and 5C is an alternative embodiment ofthe apparatus 300 of FIG. 5A wherein the proximal electrode 306 a ofFIG. 5A has been replaced with a wall-contacting electrode 306 a′. Thewall-contacting electrode can comprise a proximal attachment 312 a thatconnects the electrode to the shaft of the catheter 302 and iselectrically coupled to the pulse generator. Extensions 314 a extendfrom the proximal attachment 312 a and at least partially extend over asurface of the positioning element 304. The extensions 314 a optionallymay be selectively insulated such that only a selective portion of theextensions, e.g., the distal tips of the extensions, are electricallyactive. The electrode 306 a′ optionally may be fabricated from a slottedtube, such as a stainless steel or shape-memory (e.g., NiTi) slottedtube. Furthermore, all or a portion of the electrode may be gold-platedto improve radiopacity and/or conductivity.

As seen in FIG. 5B, the catheter 302 may be delivered over a guidewire Gto a treatment site within the patient's vessel with the electrode 306a′ positioned in a reduced profile configuration (e.g., contractedconfiguration). The catheter 302 optionally may be delivered through aguide catheter 303 to facilitate such reduced profile delivery of thewall-contacting electrode. When positioned as desired at a treatmentsite, the electrode may be expanded into contact with the vessel wall byexpanding the positioning element 304 (FIG. 5C). A monopolar or bipolar,pulsed or continuous, thermal or athermal electric field then may bedelivered across the vessel wall and between the electrodes 306 a′ and306 b to induce neuromodulation, as discussed previously. The optionalpositioning element 304 may alter impedance within the blood vessel andmore efficiently route the electrical energy across the vessel wall tothe target neural fibers

After delivery of the electric field, the electrode 306 a′ may bereturned to a contracted profile to facilitate removal of the apparatus300 from the patient. For example, the positioning element 304 may becollapsed (e.g., deflated), and the electrode 306 a′ may be contractedby withdrawing the catheter 302 within the guide catheter 303.Alternatively, the electrode may be fabricated from a shape-memorymaterial biased to the collapsed configuration, such that the electrodeself-collapses upon collapse of the positioning element.

In addition to extravascular and intravascular neuromodulation systems,intra-to-extravascular neuromodulation systems may be provided having,e.g., electrode(s) that are delivered to an intravascular position, thenat least partially passed through/across the vessel wall to anextravascular position prior to delivery of e-field therapy.Intra-to-extravascular positioning of the electrode(s) may place theelectrode(s) in closer proximity to target neural fibers during thee-field therapy compared to fully intravascular positioning of theelectrode(s). With reference to FIG. 5D, one embodiment of anintra-to-extravascular (“ITEV”) e-field system, described previously inthe '188 application, is shown.

ITEV e-field system 320 comprises a catheter 322 having (a) a pluralityof proximal electrode lumens terminating at proximal side ports 324, (b)a plurality of distal electrode lumens terminating at distal side ports326, and (c) a guidewire lumen 323. The catheter 322 preferablycomprises an equal number of proximal and distal electrode lumens andside ports. The system 320 also includes proximal needle electrodes 328that may be advanced through the proximal electrode lumens and theproximal side ports 324, as well as distal needle electrodes 329 thatmay be advanced through the distal electrode lumens and the distal sideports 326.

Catheter 322 comprises an optional expandable positioning element 330,which may comprise an inflatable balloon or an expandable basket orcage. In use, the positioning element 330 may be expanded prior todeployment of the needle electrodes 328 and 329 in order to center thecatheter 322 within the patient's vessel (e.g., within renal artery RA).Centering the catheter 322 is expected to facilitate delivery of allneedle electrodes to desired depths with to the patient's vessel (e.g.,to deliver all of the needle electrodes approximately to the samedepth). In FIG. 5D, the illustrated positioning element 330 ispositioned between the proximal side ports 324 and the distal side ports326, i.e., between the delivery positions of the proximal and distalelectrodes. However, it should be understood that positioning element330 additionally or alternatively may be positioned at a differentlocation or at multiple locations along the length of the catheter 322(e.g., at a location proximal of the side ports 324 and/or at a locationdistal of the side ports 326).

As illustrated in FIG. 5D, the catheter 322 may be advanced to atreatment site within the patients vasculature (e.g., to a treatmentsite within the patient's renal artery RA) over a guidewire (not shown)via the lumen 323. During intravascular delivery, the electrodes 328 and329 may be positioned such that their non-insulated and sharpened distalregions are positioned within the proximal and distal lumens,respectively. Once positioned at a treatment site, a medicalpractitioner may advance the electrodes via their proximal regions thatare located external to the patient. Such advancement causes the distalregions of the electrodes 328 and 329 to exit side ports 324 and 326,respectively, and pierce the wall of the patient's vasculature such thatthe electrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 328 can be connected to field generator 50 asactive electrodes and the distal electrodes 329 can serve as returnelectrodes. In this manner, the proximal and distal electrodes formbipolar electrode pairs that align the e-field therapy with alongitudinal axis or direction of the patient's vasculature. As will beapparent, the distal electrodes 329 alternatively may comprise theactive electrodes and the proximal electrodes 328 may comprise thereturn electrodes. Furthermore, the proximal and/or the distalelectrodes may comprise both active and return electrodes. Anycombination of active and distal electrodes may be utilized, as desired.

When the electrodes 328 and 329 are connected to field generator 50 andare positioned extravascularly, and with positioning element 330optionally expanded, e-field therapy may proceed to achieve desiredneuromodulation. After completion of the e-field therapy, the electrodesmay be retracted within the proximal and distal lumens, and thepositioning element 330 may be collapsed for retrieval. ITEV e-fieldsystem 320 then may be removed from the patient to complete theprocedure. Additionally or alternatively, the system may be repositionedto provide e-field therapy at another treatment site, for example, toprovide bilateral renal neuromodulation.

It is expected that e-field therapy, as well as other methods andapparatus of the present invention for neuromodulation (e.g., localizeddrug delivery, high intensity focused ultrasound, thermal techniques,etc.), whether delivered extravascularly, intravascularly,intra-to-extravascularly or a combination thereof, may, for example,effectuate irreversible electroporation or electrofusion, ablation,necrosis, and/or inducement of apoptosis, alteration of gene expression,action potential blockade or attenuation, changes in cytokineup-regulation and other conditions in target neural fibers. In somepatients, when such neuromodulatory methods and apparatus are applied torenal nerves and/or other neural fibers that contribute to renal neuralfunctions, applicants believe that the neuromodulatory effects inducedby the neuromodulation may increase urine output, decrease plasma reninlevels, decrease tissue (e.g., kidney) and/or urine catecholamines(e.g., norepinephrine), increase urinary sodium excretion, and/orcontrol blood pressure.

Neuromodulation in accordance with the present invention optionally isachieved without completely physically severing, i.e., without fullycutting, the target neural fibers. However, it should be understood thatsuch neuromodulation may functionally sever the neural fibers, eventhough the fibers may not be completely physically severed. Apparatusand methods described herein illustratively are configured forpercutaneous use. Such percutaneous use may be endoluminal,laparoscopic, a combination thereof, etc.

Although the embodiments of FIGS. 4 and 5 illustratively comprisebipolar apparatus, it should be understood that monopolar apparatusalternatively may be utilized. For example, an active monopolarelectrode may be positioned intravascularly, extravascularly orintra-to-extravascularly in proximity to target neural fibers thatcontribute to renal function. A return electrode ground pad may beattached to the exterior of the patient. Finally, e-field therapy may bedelivered between the in vivo monopolar electrode and the ground pad toeffectuate desired renal neuromodulation. Monopolar apparatusadditionally may be utilized for bilateral renal neuromodulation.

Furthermore, although the embodiments of FIGS. 4 and 5 illustrativelycomprise e-field neuromodulation apparatus, it should be understood thatalternative energy modalities may be utilized to achieve desiredneuromodulation. For example, thermal energy, high intensity focusedultrasound and/or a neuromodulatory agent may be deliveredintravascularly, extravascularly, intra-to-extravascularly, or acombination thereof to achieve the desired neuromodulation.

It may be desirable to achieve bilateral renal neuromodulation.Bilateral neuromodulation may enhance the therapeutic effect in somepatients as compared to renal neuromodulation performed unilaterally,i.e., as compared to renal neuromodulation performed on neural tissueinnervating a single kidney. For example, bilateral renalneuromodulation may further reduce clinical symptoms of heartarrhythmia, and/or of congestive heart failure, hypertension, acutemyocardial infarction, contrast nephropathy, renal disease and/or othercardio-renal diseases. FIGS. 6A-6H illustrate stages of a method forbilateral renal neuromodulation utilizing the intravascular apparatus ofFIG. 5A. However, it should be understood that such bilateralneuromodulation alternatively may be achieved utilizing theextravascular apparatus of FIG. 4, utilizing the intra-to-extravascularapparatus of FIG. 5D, or utilizing any alternative intravascularapparatus, extravascular apparatus, intra-to-extravascular apparatus(including monopolar apparatus) or combination thereof.

As seen in FIGS. 6A and 6E, a guide catheter GC and a guidewire G may beadvanced into position within, or in proximity to, either the patient'sleft renal artery LRA or right renal artery RRA. In FIG. 6A, theguidewire illustratively has been positioned in the right renal arteryRRA, but it should be understood that the order of bilateral renalneuromodulation illustrated in FIGS. 6A-6H alternatively may bereversed. Additionally or alternatively, bilateral renal neuromodulationmay be performed concurrently on both right and left neural fibers thatcontribute to renal function, as in FIGS. 7-9, rather than sequentially,as in FIG. 6.

With the guidewire and the guide catheter positioned in the right renalartery, the catheter 302 of the apparatus 360 may be advanced over theguidewire and through the guide catheter into position within theartery. As seen in FIG. 6B, the optional positioning element 304 of thecatheter 302 is in a reduced delivery configuration during delivery ofthe catheter to the renal artery. In FIG. 6C, once the catheter isproperly positioned for e-field therapy, the element 304 optionally maybe expanded into contact with the vessel wall, and the guidewire G maybe retracted from the treatment zone, e.g., may be removed from thepatient or may be positioned more proximally within the patient's aorta.

Expansion of element 304 may center or otherwise position the electrodes306 within the vessel and/or may alter impedance between the electrodes.With apparatus 300 positioned and deployed as desired, e-field therapymay be delivered, e.g., in a bipolar fashion across the electrodes 306to achieve renal neuromodulation in neural fibers that contribute toright renal function, e.g., to at least partially achieve renaldenervation of the right kidney. As illustrated by propagation lines Li,the electric field may be aligned with a longitudinal dimension of therenal artery RA and may pass across the vessel wall. The alignment andpropagation path of the electric field is expected to preferentiallymodulate cells of the target renal nerves without unduly affectingnon-target arterial smooth muscle cells.

As seen in FIG. 6D, after completion of the e-field therapy, the element304 may be collapsed back to the reduced delivery profile, and thecatheter 302 may be retracted from the right renal artery RRA, forexample, to a position in the guide catheter GC within the patient'sabdominal aorta. Likewise, the guide catheter GC may be retracted to aposition within the patient's aorta. The retracted guide catheter may berepositioned, e.g., rotated, such that its distal outlet is generallyaligned with the left renal artery LRA. The guidewire G then may bereadvanced through the catheter 302 and the guide catheter CC to aposition within the left renal artery LRA, as shown in FIG. 6E (as willbe apparent, the order of advancement of the guidewire and the guidecatheter optionally may be reversed when accessing either renal artery).

Next, the catheter 302 may be re-advanced over the guidewire and throughthe guide catheter into position within the left renal artery, as shownin FIG. 6F. In FIG. 6G, once the catheter is properly positioned fore-field therapy, the element 304 optionally may be expanded into contactwith the vessel wall, and the guidewire G may be retracted to a positionproximal of the treatment site. Electric field therapy then may bedelivered in a bipolar fashion across the electrodes 306, for example,along propagation lines Li, to achieve renal neuromodulation in neuralfibers that contribute to left renal function, e.g., to at leastpartially achieve renal denervation of the left kidney. As seen in FIG.6H, after completion of the bilateral e-field therapy, the element 304may be collapsed back to the reduced delivery profile, and the catheter302, as well as the guidewire G and the guide catheter GC, may beremoved from the patient to complete the bilateral renal neuromodulationprocedure.

As discussed previously, bilateral renal neuromodulation optionally maybe performed concurrently on fibers that contribute to both right andleft renal function. FIGS. 7A and 7B illustrate embodiments of apparatus300 for performing concurrent bilateral renal neuromodulation. In theembodiment of FIG. 7A, apparatus 300 comprises dual e-field therapycatheters 302, as well as dual guidewires and guide catheters GC. Onecatheter 302 is positioned within the right renal artery RRA, and theother catheter 302 is positioned within the left renal artery LRA. Withcatheters 302 positioned in both the right and left renal arteries,e-field therapy may be delivered concurrently by the catheters 302 toachieve concurrent bilateral renal neuromodulation, illustratively viaan intravascular approach.

In one example, separate arteriotomy sites may be made in the patient'sright and left femoral arteries for percutaneous delivery of the twocatheters 302. Alternatively, both catheters 302 may be deliveredthrough a single femoral access site, either through dual guidecatheters or through a single guide catheter. FIG. 7B illustrates anexample of apparatus 300 for concurrent bilateral renal neuromodulationutilizing single arteriotomy access site. In the example of FIG. 7B,both catheters 302 are delivered through a custom bifurcated guidecatheter GC′ having a bifurcated distal region for concurrentlydelivering the catheters 302 to the right and left renal arteries.Concurrent (or sequential) bilateral e-field therapy then may proceed.

FIG. 8 illustrates additional methods and apparatus for concurrentbilateral renal neuromodulation. In FIG. 8, an embodiment ofextravascular apparatus 200 comprising dual probes 210 and electrodes212. The electrodes have been positioned in the vicinity of both theleft renal artery LRA and the right renal artery RRA. Electric fieldtherapy may be delivered concurrently by the electrodes 212 to achieveconcurrent bilateral renal neuromodulation, illustratively via anextravascular approach.

As will be apparent, intra-to-extravascular apparatus alternatively maybe utilized for bilateral renal neuromodulation. Such bilateral renalneuromodulation may be performed sequentially, concurrently or acombination thereof. For example, ITEV e-field system 320 of FIG. 5D maybe utilized for bilateral renal neuromodulation.

Additional methods and apparatus for achieving renal neuromodulation,e.g., via localized drug delivery (such as by a drug pump or infusioncatheter) or via use of a stimulation electric field, etc, also mayutilized. Examples of such methods and apparatus have been describedpreviously, for example, in co-owned and co-pending U.S. patentapplication Ser. No. 10/408,565, filed Apr. 8, 2003, and in U.S. Pat.No. 6,976,174, both of which have been incorporated herein by reference.

FIG. 9 shows one example of methods and apparatus for achieving renalneuromodulation (illustratively bilateral) via fully implantedapparatus. In FIG. 9, an element 400 has been implanted within thepatient. Conduits 402 a and 402 b are connected to the element 400 andextend to the vicinity of the right renal artery RRA and the left renalartery LRA, respectively. The element 400 generates or contains aneuromodulatory therapy capable of modulating neural fibers thatcontribute to renal function, and the conduits 402 deliver the therapyto the vicinity of the renal arteries. Delivering the therapy throughthe conduits 402 a and 402 b may achieve bilateral renalneuromodulation. Such therapy delivery may be conducted concurrently orsequentially, as well as continuously or intermittently, as desired, inorder to provide concurrent or sequential, continuous or intermittent,renal neuromodulation, respectively.

In one embodiment, the element 400 comprises an implantableneurostimulator or a pacemaker-type device, and the conduits 402comprise electrical leads that are coupled to the neurostimulator fordelivery of an electric field, such as a pulsed or continuous electricfield, a stimulation electric field, a thermal or non-thermal electricfield, to the target neural fibers. In another embodiment, the element400 comprises an implantable drug pump, and the conduits 402 comprisedrug delivery catheters for delivery of neuromodulatory agent(s) ordrug(s) from the pump to the target neural fibers. In yet anotheralternative embodiment, electrical techniques may be combined withdelivery of neuromodulatory agent(s) to achieve desired renalneuromodulation.

In an alternative embodiment of the apparatus of FIG. 9, conduits 402 aand 402 b may only temporarily be positioned at a desired location,e.g., for acute delivery of the neuromodulatory therapy, e.g., from anexternal field generator or from an external drug reservoir, such as asyringe. Such temporary positioning may comprise, for example,intravascular, extravascular and/or intra-to-extravascular placement ofthe catheters.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. It is intended in the appended claims to cover allsuch changes and modifications that fall within the true spirit andscope of the invention.

1. A method for treating heart arrhythmia, the method comprising:introducing a modulation instrument proximate a neural fiber thatcontributes to renal function of a kidney of a patient; and deliveringenergy and/or a neuromodulatory agent to the neural fiber via themodulation instrument in order to modulate a function of the neuralfiber, thereby systemically reducing sympathetic tone in the patient. 2.The method of claim 1, wherein delivering energy further comprisesdelivering an electric field.
 3. The method of claim 2, whereindelivering the electric field further comprises delivering a pulsedelectric field.
 4. The method of claim 2, wherein delivering theelectric field further comprises delivering a continuous electric field.5. The method of claim 1, wherein delivering a neuromodulatory agentfurther comprises delivering a drug to the neural fiber.
 6. The methodof claim 1, wherein modulating the function of the neural fiber furthercomprises at least partially denervating the kidney.
 7. The method ofclaim 1, wherein modulating the function of the neural fiber furthercomprises inducing an effect in the neural fiber chosen from the groupconsisting of irreversible electroporation, electrofusion, ablation,necrosis, apoptosis, gene expression alteration, cytokine up-regulationalteration, and combinations thereof.
 8. The method of claim 1, whereindelivering energy further comprises delivering thermal energy.
 9. Themethod of claim 1, wherein delivering energy further comprisesdelivering high intensity focused ultrasound.
 10. The method of claim 1,wherein systemically reducing sympathetic tone in the patient furthercomprises decreasing a load on a heart of the patient.
 11. A method fortreating heart arrhythmia, the method comprising: introducing amodulation instrument proximate a neural fiber that contributes to renalfunction of a kidney of a patient; and delivering energy and/or aneuromodulatory agent to the neural fiber via the modulation instrumentin order to modulate a function of the neural fiber, thereby decreasinga load on a heart of the patient.
 12. The method of claim 11, whereindelivering energy further comprises delivering an electric field. 13.The method of claim 12, wherein delivering the electric field furthercomprises delivering a pulsed electric field.
 14. The method of claim12, wherein delivering the electric field further comprises delivering acontinuous electric field.
 15. The method of claim 11, whereindelivering the neuromodulatory agent further comprises delivering a drugto the neural fiber.
 16. The method of claim 11, wherein modulating thefunction of the neural fiber further comprises at least partiallydenervating the kidney.
 17. The method of claim 11, wherein modulatingthe function of the neural fiber further comprises inducing an effect inthe neural fiber chosen from the group consisting of irreversibleelectroporation, electrofusion, ablation, necrosis, apoptosis, geneexpression alteration, cytokine up-regulation alteration, andcombinations thereof.
 18. The method of claim 11, wherein delivering theenergy further comprises delivering thermal energy.
 19. The method ofclaim 11, wherein delivering the energy further comprises deliveringhigh intensity focused ultrasound.
 20. The method of claim 11, whereindecreasing the load on the heart of the patient further comprisessystemically reducing sympathetic tone in the patient. 21-48. (canceled)